Vaccination with live attenuated classical swine fever virus (CSFV) vaccines can rapidly confer protection in the absence of neutralizing antibodies. With an aim of providing information on the cellular mechanisms that may mediate this protection, we explored the interaction of porcine natural killer (NK) cells and ?? T cells with CSFV. Both NK and ?? T cells were refractory to infection with attenuated or virulent CSFV, and no stimulatory effects, as assessed by the expression of major histocompatibility complex (MHC) class II (MHC-II), perforin, and gamma interferon (IFN-?), were observed when the cells were cultured in the presence of CSFV. Coculture with CSFV and myeloid dendritic cells (mDCs) or plasmacytoid dendritic cells (pDCs) showed that pDCs led to a partial activation of both NK and ?? T cells, with upregulation of MHC-II being observed. An analysis of cytokine expression by infected DC subsets suggested that this effect was due to IFN-? secreted by infected pDCs. These results were supported by ex vivo analyses of NK and ?? T cells in the tonsils and retropharyngeal lymph nodes from pigs that had been vaccinated with live attenuated CSFV and/or virulent CSFV. At 5 days postchallenge, there was evidence of significant upregulation of MHC-II but not perforin on NK and ?? T cells, which was observed only following a challenge of the unvaccinated pigs and correlated with increased CSFV replication and IFN-? expression in both the tonsils and serum. Together, these data suggest that it is unlikely that NK or ?? T cells contribute to the cellular effector mechanisms induced by live attenuated CSFV.
Lateral humeral condyle fractures account for 17 % of the distal humeral condyle fractures. Displaced and/or rotated fractures require appropriate reduction and stabilisation. There are, however, a number of controversies in the surgical management of these patients. The aim of the present study was to review the results of patients with a displaced lateral humeral condyle fracture treated with open reduction and internal fixation (ORIF). We retrospectively reviewed children treated with ORIF of lateral humeral condyle fractures at a single institution over a period of 13 years. All cases were identified through the trauma register. Case notes and radiographs were retrieved. Fracture classification, mode of fixation, time to union, and final outcomes at the latest follow-up were reviewed. One hundred and five lateral condyle fractures were identified in 76 male and 29 female patients. Average age was 6.2 years. Ninety-two were Milch type II and 13 Milch type I. According to the Jacob's classification, 38 were type II and 67 type III. All fractures were treated with open reduction and fixation with K-wires. Average time to radiological union was 33 days. Follow-up ranged between 2 and 8 years (average 3.2 years). Radiological hypertrophy of the lateral condyle was present in 45 cases (42 %). Three patients developed a pseudo-cubitus varus deformity. Further four patients developed a true cubitus varus. There was one case of superficial infection of the K-wires and one case of delayed union. At the latest follow-up, 96 % of the patients achieved an excellent final result and 4 % a good final result. Our results demonstrate that fracture union and excellent final outcomes can be expected in all patients using our protocol, whereby all patients with a displaced fracture are managed by ORIF with K-wire fixation, with the wires only being removed after there is evidence of radiological union. Compared to recent reports of closed reduction internal fixation, this series demonstrates good results with no complications directly relating to the open reduction technique. Level of evidence Case series, Level IV.
Developmental dysplasia of the hip (DDH) is rarely encountered in the native sub-Saharan African population. We present a retrospective review of the incidence of symptomatic DDH in Malawi and a systematic review of the role of back-carrying as a potential influence of prevalence in this population group.
The porcine reproductive and respiratory syndrome virus (PRRSV) is a rapidly evolving and diversifying pathogen necessitating the development of improved vaccines. Immunity to PRRSV is not well understood although there are data suggesting that virus-specific T cell IFN-? responses play an important role. We therefore aimed to better characterise the T cell response to genotype 1 (European) PRRSV by utilising a synthetic peptide library spanning the entire proteome and a small cohort of pigs rendered immune to PRRSV-1 Olot/91 by repeated experimental infection. Using an IFN-? ELISpot assay as a read-out, we were able to identify 9 antigenic regions on 5 of the viral proteins and determine the corresponding responder T cell phenotype. The diversity of the IFN-? response to PRRSV proteins suggests that antigenic regions are scattered throughout the proteome and no one single antigen dominates the T cell response. To address the identification of well-conserved T cell antigens, we subsequently screened groups of pigs infected with a closely related avirulent PRRSV-1 strain (Lelystad) and a divergent virulent subtype 3 strain (SU1-Bel). Whilst T cell responses from both groups were observed against many of the antigens identified in the first study, animals infected with the SU1-Bel strain showed the greatest response against peptides representing the non-structural protein 5. The proteome-wide peptide library screening method used here, as well as the antigens identified, warrant further evaluation in the context of next generation vaccine development.
Better understanding of the brain regions involved in performing laparoscopic surgery is likely to provide important insights for improving laparoscopic training and assessment in the future. To our knowledge, this is the first study using real Fundamentals of Laparoscopy Training (FLS)-based laparoscopic surgery training tasks in the functional magnetic resonance imaging (fMRI) environment to provide extensive characterization of the brain regions involved in this specific task execution.
Natural killer (NK) cells are important players in the innate immune response against influenza A virus and the activating receptor NKp46, which binds hemagglutinin on the surface of infected cells, has been assigned a role in this context. As pigs are natural hosts for influenza A viruses and pigs possess both NKp46- and NKp46+ NK cells, they represent a good animal model for studying the role of the NKp46 receptor during influenza. We explored the role of NK cells in piglets experimentally infected with 2009 pandemic H1N1 influenza virus by flow cytometric analyses of cells isolated from blood and lung tissue and by immunostaining of lung tissue sections. The number of NKp46+ NK cells was reduced while NKp46- NK cells remained unaltered in the blood 1-3 days after infection. In the lungs, the intensity of NKp46 expression on NK cells was increased during the first 3 days, and areas where influenza virus nucleoprotein was detected were associated with increased numbers of NKp46+ NK cells when compared to uninfected areas. NKp46+ NK cells in the lung were neither found to be infected with influenza virus nor to be undergoing apoptosis. The binding of porcine NKp46 to influenza virus infected cells was verified in an in vitro assay. These data support the involvement of porcine NKp46+ NK cells in the local immune response against influenza virus.
Sport-related concussions are now recognized as a major public health concern: the number of participants in sport and recreation is growing, possibly playing their games faster, and there is heightened public awareness of injuries to some high-profile athletes. However, many clinicians still rely on subjective symptom reports for the clinical determination of recovery. Relying on subjective symptom reports can be problematic, as it has been shown that some concussed athletes may downplay their symptoms. The use of neuropsychological (NP) testing has enabled clinicians to measure the effects and extent of impairment following concussion more precisely, providing more objective metrics for determining recovery. Nevertheless, there is a remaining concern that brain abnormalities may exist beyond the point at which individuals achieve recovery in self-reported symptoms and cognition measured by NP testing. Our understanding of brain recovery after concussion is important, not only from a neuroscience perspective, but also from the perspective of clinical decision-making for safe return-to-play. A number of advanced neuroimaging tools, including blood oxygen level dependent functional magnetic resonance imaging (fMRI), have independently yielded early information on abnormal brain functioning. In the two cases presented in this article, we report contrasting brain activation patterns and recovery profiles using fMRI. Importantly, fMRI was conducted using adapted versions of the most sensitive computerized NP tests administered in our current clinical practice to determine impairments and recovery after sport-related concussion. One of the cases is consistent with the concept of lagging brain recovery.
Planar electrodes are increasingly used in a variety of neural stimulation techniques such as epidural spinal cord stimulation, epidural cortical stimulation, transcranial direct current stimulation and functional electric stimulation. Recently, optimized electrode geometries have been shown to increase the efficiency of neural stimulation by maximizing the variation of current density on the electrode surface. In the present work, a new family of modified fractal electrode geometries is developed to increase the neural activation function and enhance the efficiency of neural stimulation. It is hypothesized that the key factor in increasing the activation function in the tissue adjacent to the electrode is to increase the "edginess" of the electrode surface, a concept that is explained and quantified by fractal mathematics. Rigorous finite element simulations were performed to compute the distribution of electric potential produced by proposed geometries, demonstrating that the neural activation function was significantly enhanced in the tissue. The activation of 800 model axons positioned around the electrodes was also quantified, showing that modified fractal geometries yielded a 22% reduction in input power consumption while maintaining the same level of neural activation. The results demonstrate the feasibility of increasing stimulation efficiency using modified fractal geometries beyond the levels already reported in the literature.
The cerebellum, which is important for movement control and planning, is often affected by many neurological conditions. Until now there has been limited information regarding how the function of the cerebellum impacts driving ability. This study used fMRI with an integrated virtual reality driving simulator to determine which aspects of driving performance are related to the cerebellum in healthy drivers (Experiment 1). It also investigated drivers with focal cerebellar lesions to identify how damage to this brain region impairs driving abilities. The results showed that cerebellar functioning is responsible for motor-speed coordination and complex temporal-motor integration necessary to execute driving behaviours. As predicted, drivers with cerebellar damage, showed significantly compromised speed control during basic driving conditions, whereas their ability to perform during interactive driving situations was preserved. New insights into neural mechanisms and brain plasticity regarding driving behaviour are discussed. Strategies in assessing and rehabilitating drivers with related neurological conditions are provided.
In Australia, higher rates of chronic hepatitis B (HBsAg) have been reported among Aboriginal and Torres Strait Islander (Indigenous) compared with non-Indigenous people. In 2000, the Australian government implemented a universal infant/adolescent hepatitis B vaccination program. We undertook a systematic review and meta-analysis to assess the disparity of HBsAg prevalence between Indigenous and non-Indigenous people, particularly since 2000.
Vaccination with live attenuated classical swine fever virus (CSFV) induces solid protection after only 5 days, which has been associated with virus-specific T cell gamma interferon (IFN-?) responses. In this study, we employed flow cytometry to characterize T cell responses following vaccination and subsequent challenge infections with virulent CSFV. The CD3(+) CD4(-) CD8(hi) T cell population was the first and major source of CSFV-specific IFN-?. A proportion of these cells showed evidence for cytotoxicity, as evidenced by CD107a mobilization, and coexpressed tumor necrosis factor alpha (TNF-?). To assess the durability and recall of these responses, a second experiment was conducted where vaccinated animals were challenged with virulent CSFV after 5 days and again after a further 28 days. While virus-specific CD4 T cell (CD3(+) CD4(+) CD8?(+)) responses were detected, the dominant response was again from the CD8 T cell population, with the highest numbers of these cells being detected 14 and 7 days after the primary and secondary challenges, respectively. These CD8 T cells were further characterized as CD44(hi) CD62L(-) and expressed variable levels of CD25 and CD27, indicative of a mixed effector and effector memory phenotype. The majority of virus-specific IFN-?(+) CD8 T cells isolated at the peaks of the response after each challenge displayed CD107a on their surface, and subpopulations that coexpressed TNF-? and interleukin 2 (IL-2) were identified. While it is hoped that these data will aid the rational design and/or evaluation of next-generation marker CSFV vaccines, the novel flow cytometric panels developed should also be of value in the study of porcine T cell responses to other pathogens/vaccines.
The unique configuration of periprosthetic femoral fractures (PFFs) is a major determinant of the subsequent management. The aim of this preliminary study was to investigate potential relationships between fracture angle (FA), fracture level (FL) and bone quality of Vancouver type B PFF. The FA, FL and the canal thickness ratio (CTR) were quantified for 27 patient X-rays. The CTR is an indicator of the underlying bone quality. Relationships between these factors were studied for the whole X-ray set, for a subgroup involving fracture above the tip of the stem and for subgroups with stable and unstable implants. When considering all cases, no significant correlation was found between the FA and any other measurement. Considering only cases with unstable implants, a statistically significant correlation was found between the FA and the FL (R(2)=0.489, p=0.002). No correlation was found between FA and any other measurement for stable implants suggesting that FA could be considered as an independent factor when classifying B1 fractures. Considering all cases, a weak correlation was found between CTR and FL (R(2)=0.152, p=0.044) suggesting that fractures below the tip of the stem may indicate a lower bone quality. This preliminary study suggests that the effect of FA on the optimal management of Vancouver type B1 fractures could be considered, independent of the quality of the bone or fracture position. Furthermore, fractures around or below the tip of the stem may suggest a poor bone quality. Larger number of patients is required to confirm these initial findings.
When people simultaneously draw lines with one hand and circles with the other hand, both trajectories tend to assume an oval shape, showing that hand motor programs interact (the so-called "bimanual coupling effect"). The aim of the present study was to investigate how motor parameters (drawing trajectories) and the related brain activity vary during bimanual movements both in real execution and in motor imagery tasks. In the Real modality, subjects performed right hand movements (lines) and, simultaneously, Congruent (lines) or Non-congruent (circles) left hand movements. In the Imagery modality, subjects performed only right hand movements (lines) and, simultaneously, imagined Congruent (lines) or Non-congruent (circles) left hand movements. Behavioral results showed a similar interference of both the real and the imagined circles on the actually executed lines, suggesting that the coupling effect also pertains to motor imagery. Neuroimaging results showed that a prefrontal-parietal network, mostly involving the pre-Supplementary Motor Area (pre-SMA) and the posterior parietal cortex (PPC), was significantly more active in Non-congruent than in Congruent conditions, irrespective of task (Real or Imagery). The data also confirmed specific roles of the right superior parietal lobe (SPL) in mediating spatial interference, and of the left PPC in motor imagery. Collectively, these findings suggest that real and imagined Non-congruent movements activate common circuits related to the intentional and predictive operation generating bimanual coupling, in which the pre-SMA and the PPC play a crucial role.
Infection of chickens with low pathogenicity avian influenza (LPAI) virus results in mild clinical signs while infection with highly pathogenic avian influenza (HPAI) viruses causes death of the birds within 36-48 hours. Since natural killer (NK) cells have been shown to play an important role in influenza-specific immunity, we hypothesise that NK cells are involved in this difference in pathogenicity. To investigate this, the role of chicken NK-cells in LPAI virus infection was studied. Next activation of lung NK cells upon HPAI virus infection was analysed. Infection with a H9N2 LPAI virus resulted in the presence of viral RNA in the lungs which coincided with enhanced activation of lung NK cells. The presence of H5N1 viruses, measured by detection of viral RNA, did not induce activation of lung NK cells. This suggests that decreased NK-cell activation may be one of the mechanisms associated with the enhanced pathogenicity of H5N1 viruses.
Pigs are thought to play a role in the adaptation of avian influenza (AI) viruses to mammalian hosts. To better understand this mechanism and to identify key mutations two highly pathogenic AI (HPAI) viruses (H5N1 and H7N7) were grown in pig cells, To mimic the pressure of an immune response, these viruses were grown in the presence of antiserum to the homologous virus or porcine IFN-?. Mutations were identified in both viruses grown in vitro in the presence and absence of antisera or IFN-? and included the PB2 mutations, E627K or 627E,D701N, described previously as requirements for the adaptation of AI viruses to mammalian species. Additional mutations were also identified in PB1, HA, NP and M genes for viruses passaged in the presence of immune pressure. The infectivity of these viruses was then assessed using ex vivo pig bronchi and lung organ cultures. For lung explants, higher levels of virus were detected in organ cultures infected with H5N1 HPAI viruses passaged in pig cell lines regardless of the presence or absence of homologous antisera or IFN-? when compared with the wild-type parental viruses. No infection was observed for any of the H7N7 HPAI viruses. These results suggest that the mutations identified in H5N1 HPAI viruses may provide a replication or infection advantage in pigs in vivo and that pigs may continue to play an important role in the ecology of influenza A viruses including those of avian origin.
The incidence of gram-negative bacterial haematogenous vertebral osteomyelitis (GNB HVO) is increasing. We performed a retrospective cohort study of patients with this type of infection in an effort to gain an improved understanding of the current clinical presentation, management and outcome.
Cigarette smoke has negative effects on bone metabolism and fracture repair. However, no study has reviewed effects of nicotine on bone and fracture repair independent of other constituents of cigarette smoke. The authors review the existing evidence of the effect of nicotine on bone and bone cells and fracture repair, drawing conclusions relevant to clinical practice and future research.
Introduction: Non-invasive measurements of brain activity have an important role to play in understanding driving ability. The current study aimed to identify the neural underpinnings of human driving behavior by visualizing the areas of the brain involved in driving under different levels of demand, such as driving while distracted or making left turns at busy intersections.Materials and Methods: To capture brain activity during driving, we placed a driving simulator with a fully functional steering wheel and pedals in a 3.0 Tesla functional magnetic resonance imaging (fMRI) system. To identify the brain areas involved while performing different real-world driving maneuvers, participants completed tasks ranging from simple (right turns) to more complex (left turns at busy intersections). To assess the effects of driving while distracted, participants were asked to perform an auditory task while driving analogous to speaking on a hands-free device and driving.Results: A widely distributed brain network was identified, especially when making left turns at busy intersections compared to more simple driving tasks. During distracted driving, brain activation shifted dramatically from the posterior, visual and spatial areas to the prefrontal cortex.Conclusions: Our findings suggest that the distracted brain sacrificed areas in the posterior brain important for visual attention and alertness to recruit enough brain resources to perform a secondary, cognitive task. The present findings offer important new insights into the scientific understanding of the neuro-cognitive mechanisms of driving behavior and lay down an important foundation for future clinical research.
The overall incidence of periprosthetic femoral fractures (PPF) is between 0.1 and 6 % of all total hip arthroplasties. Locking compression plates (LCP) have been used for the treatment of Vancouver B1 PPFs with variable results. The aim of this study is to examine the literature on locking plate failure rates, mode and reasons for failure.
The developed world faces major socioeconomic and medical challenges associated with motor vehicle accidents caused by risky driving. Functional magnetic resonance imaging (fMRI) of individuals using virtual reality driving simulators may provide an important research tool to assess driving safety, based on brain activity and behavior.
Mesenchymal stem cells (MSCs) are multipotent stromal cells characterized by their ability to differentiate into adipocytes, chondrocytes, osteocytes and a number of other lineages. Investigation into their use has increased in recent years as characterization of their immunomodulatory properties has developed, and their role in the pathophysiology of joint disease has been suggested.
Vaccination with live attenuated classical swine fever virus (CSFV) vaccines induces a rapid onset of protection which has been associated with virus-specific CD8 T cell IFN-? responses. In this study, we assessed the specificity of this response, by screening a peptide library spanning the CSFV C-strain vaccine polyprotein to identify and characterise CD8 T cell epitopes. Synthetic peptides were pooled to represent each of the 12 CSFV proteins and used to stimulate PBMC from four pigs rendered immune to CSFV by C-strain vaccination and subsequently challenged with the virulent Brescia strain. Significant IFN-? expression by CD8 T cells, assessed by flow cytometry, was induced by peptide pools representing the core, E2, NS2, NS3 and NS5A proteins. Dissection of these antigenic peptide pools indicated that, in each instance, a single discrete antigenic peptide or pair of overlapping peptides was responsible for the IFN-? induction. Screening and titration of antigenic peptides or truncated derivatives identified the following antigenic regions: core241-255 PESRKKLEKALLAWA and NS31902-1912 VEYSFIFLDEY, or minimal length antigenic peptides: E2996-1003 YEPRDSYF, NS21223-1230 STVTGIFL and NS5A3070-3078 RVDNALLKF. The epitopes are highly conserved across CSFV strains and variable sequence divergence was observed with related pestiviruses. Characterisation of epitope-specific CD8 T cells revealed evidence of cytotoxicity, as determined by CD107a mobilisation, and a significant proportion expressed TNF-? in addition to IFN-?. Finally, the variability in the antigen-specificity of these immunodominant CD8 T cell responses was confirmed to be associated with expression of distinct MHC class I haplotypes. Moreover, recognition of NS21223-1230 STVTGIFL and NS31902-1912 VEYSFIFLDEY by a larger group of C-strain vaccinated animals showed that these peptides could be restricted by additional haplotypes. Thus the antigenic regions and epitopes identified represent attractive targets for evaluation of their vaccine potential against CSFV.
Planar electrodes are increasingly used in therapeutic neural stimulation techniques such as functional electrical stimulation, epidural spinal cord stimulation (ESCS), and cortical stimulation. Recently, optimized electrode geometries have been shown to increase the efficiency of neural stimulation by increasing the variation of current density on the electrode surface. In the present work, a new family of modified fractal electrode geometries is developed to enhance the efficiency of neural stimulation. It is shown that a promising approach in increasing the neural activation function is to increase the "edginess" of the electrode surface, a concept that is explained and quantified by fractal mathematics. Rigorous finite element simulations were performed to compute electric potential produced by proposed modified fractal geometries. The activation of 256 model axons positioned around the electrodes was then quantified, showing that modified fractal geometries required a 22% less input power while maintaining the same level of neural activation. Preliminary in vivo experiments investigating muscle evoked potentials due to median nerve stimulation showed encouraging results, supporting the feasibility of increasing neural stimulation efficiency using modified fractal geometries.
The global burden of stroke continues to grow. Although stroke prevention strategies (e.g., medications, diet, and exercise) can contribute to risk reduction, options for acute interventions (e.g., thrombolytic therapy for ischemic stroke) are limited to the minority of patients. The remaining patients are often left with profound neurological disabilities that substantially impact quality of life, economic productivity, and increase caregiver burden. In the last decade, however, the future outlook for such patients has been tempered by movement toward the view that the brain is capable of reorganizing after injury. Many now view brain recovery after stroke as an area of scientific research with large potential for therapeutic advances, far into the future (Broderick and William, 2004). As a probe of brain anatomy, function and physiology, magnetic resonance imaging (MRI) is a non-invasive and highly versatile modality that promises to play a particularly important role in such research. Here we provide a basic review of MRI physical principles and applications for assessing stroke, looking toward the future role MRI may play in improving stroke rehabilitation methods and stroke recovery.
Recent evidence suggests that antibiotics exert direct effects on bone at a cellular level, disrupting mitochondrial function and cell activity. This comprehensive literature review aims to evaluate evidence for the effects of antibiotics and antimicrobials on bone and discuss the clinical implications.
Functional magnetic resonance imaging (fMRI) is limited by sensitivity to millimetre-scale head motion. Adaptive correction is a strategy to adjust the imaging plane in response to measured head motion, thereby suppressing motion artifacts. This strategy should correct for motion in all six degrees of freedom and also holds promise for through-plane motion that creates "spin-history" artifact that cannot easily be removed by postprocessing methods. Improved quantitative understanding of the MRI signal behavior associated with spin-history artifact would be useful for implementing adaptive correction robustly.
Blood oxygenation level dependent (BOLD) contrast in functional magnetic resonance imaging (fMRI) can be enhanced using multi-echo imaging and postprocessing techniques that combine the echoes in weighted summation. Here, existing echo-weighting methods are reassessed in the context of an explicit physiological noise model, and a new method is introduced: weights that scale linearly with echo time. Additionally, a method using data-driven weights defined using principal component analysis (PCA) is included for comparison. Differences in BOLD contrast enhancement between methods were compared analytically where possible, and using Monte Carlo simulations for different noise conditions and different combinations of acquisition parameters. The comparisons were also validated through densely sampled (256-echo) multi-echo fMRI experimental data acquired at 1.5T and 3.0T. Results indicated that the contrast-to-noise ratio (CNR) of the studied weighting methods have a strong dependence on the physiological noise, echo spacing and the width of the sampling window. With low noise correlations between echoes, contrast gain for all weighting methods was shown to have a square root dependence on the echo sampling density, and in typical experimental noise conditions, increasing the sampling window beyond 3·T2* produced marginal additional benefit. Simulations and experiments also emphasized that noise correlations between echoes are likely the main factor limiting the potential CNR gains achievable by densely sampled multi-echo fMRI.
Subject-specific artifacts caused by head motion and physiological noise are major confounds in BOLD fMRI analyses. However, there is little consensus on the optimal choice of data preprocessing steps to minimize these effects. To evaluate the effects of various preprocessing strategies, we present a framework which comprises a combination of (1) nonparametric testing including reproducibility and prediction metrics of the data-driven NPAIRS framework (Strother et al. : NeuroImage 15:747-771), and (2) intersubject comparison of SPM effects, using DISTATIS (a three-way version of metric multidimensional scaling (Abdi et al. : NeuroImage 45:89-95). It is shown that the quality of brain activation maps may be significantly limited by sub-optimal choices of data preprocessing steps (or "pipeline") in a clinical task-design, an fMRI adaptation of the widely used Trail-Making Test. The relative importance of motion correction, physiological noise correction, motion parameter regression, and temporal detrending were examined for fMRI data acquired in young, healthy adults. Analysis performance and the quality of activation maps were evaluated based on Penalized Discriminant Analysis (PDA). The relative importance of different preprocessing steps was assessed by (1) a nonparametric Friedman rank test for fixed sets of preprocessing steps, applied to all subjects; and (2) evaluating pipelines chosen specifically for each subject. Results demonstrate that preprocessing choices have significant, but subject-dependant effects, and that individually-optimized pipelines may significantly improve the reproducibility of fMRI results over fixed pipelines. This was demonstrated by the detection of a significant interaction with motion parameter regression and physiological noise correction, even though the range of subject head motion was small across the group (? 1 voxel). Optimizing pipelines on an individual-subject basis also revealed brain activation patterns either weak or absent under fixed pipelines, which has implications for the overall interpretation of fMRI data, and the relative importance of preprocessing methods.
Theileria parva causes an acute fatal disease in cattle, but infections are asymptomatic in the African buffalo (Syncerus caffer). Cattle can be immunized against the parasite by infection and treatment, but immunity is partially strain specific. Available data indicate that CD8(+) T lymphocyte responses mediate protection and, recently, several parasite antigens recognised by CD8(+) T cells have been identified. This study set out to determine the nature and extent of polymorphism in two of these antigens, Tp1 and Tp2, which contain defined CD8(+) T-cell epitopes, and to analyse the sequences for evidence of selection.
In patients suffering from schizophrenia and bipolar disorder, antipsychotics are the mainstay of treatment worldwide. By blocking D(2) brain mesolimbic receptors, antipsychotics are believed to reduce and control psychotic experiences, but recent evidence has suggested that they may also have adverse effects on bone mineral architecture and fracture incidence.
Although parasite strain-restricted CD8 T cell responses have been described for several protozoa, the precise role of antigenic variability in immunity is poorly understood. The tick-borne protozoan parasite Theileria annulata infects leukocytes and causes an acute, often fatal lymphoproliferative disease in cattle. Building on previous evidence of strain-restricted CD8 T cell responses to T. annulata, this study set out to identify and characterize the variability of the target antigens. Three antigens were identified by screening expressed parasite cDNAs with specific CD8 T cell lines. In cattle expressing the A10 class I major histocompatibility complex haplotype, A10-restricted CD8 T cell responses were shown to be focused entirely on a single dominant epitope in one of these antigens (Ta9). Sequencing of the Ta9 gene from field isolates of T. annulata demonstrated extensive sequence divergence, resulting in amino acid polymorphism within the A10-restricted epitope and a second A14-restricted epitope. Statistical analysis of the allelic sequences revealed evidence of positive selection for amino acid substitutions within the region encoding the CD8 T cell epitopes. Sequence differences in the A10-restricted epitope were shown to result in differential recognition by individual CD8 T cell clones, while clones also differed in their ability to recognize different alleles. Moreover, the representation of these clonal specificities within the responding CD8 T cell populations differed between animals. As well as providing an explanation for incomplete protection observed after heterologous parasite challenge of vaccinated cattle, these results have important implications for the choice of antigens for the development of novel subunit vaccines.
Theileria parva antigens recognized by cytotoxic T lymphocytes (CTLs) are prime vaccine candidates against East Coast fever in cattle. A strategy for enhancing induction of parasite-specific T cell responses by increasing recruitment and activation of dendritic cells (DCs) at the immunization site by administration of bovine Flt3L and GM-CSF prior to inoculation with DNA vaccine constructs and MVA boost was evaluated. Analysis of immune responses showed induction of significant T. parva-specific proliferation, and IFN-?-secreting CD4(+) and CD8(+) T cell responses in immunized cattle. However, antigen-specific CTLs were not detected. Following lethal challenge, 5/12 immunized cattle survived by day 21, whereas all the negative controls had to be euthanized due to severe disease, indicating a protective effect of the vaccine (p<0.05). The study demonstrated the potential of this technology to elicit significant MHC class II and class I restricted IFN-?-secreting CD4(+) and CD8(+) T cells to defined vaccine candidate antigens in a natural host, but also underscores the need to improve strategies for eliciting protective CTL responses.
Language and certain aspects of motor control are typically served by the left hemisphere, whereas visuospatial and attentional control are lateralized to the right. Here a (visuo)motor tracing task was used to identify hemispheric lateralization beyond the general, contralateral organization of the motor system. Functional magnetic resonance imaging (fMRI) was applied in 40 male right-handers (19-30 yrs) during line tracing with dominant and nondominant hand, with and without visual guidance. Results revealed a network of areas activating more in the right than left hemisphere, irrespective of the effector. Inferior portions of frontal gyrus and parietal lobe overlapped largely with a previously described ventral attention network responding to unexpected or behaviourally relevant stimuli. This demonstrates a hitherto unreported functionality of this circuit that also seems to activate when spatial information is continuously exploited to adapt motor behaviour. Second, activation of left dorsal premotor and postcentral regions during tracing with the nondominant left hand was more pronounced than that in their right hemisphere homologues during tracing with the dominant right hand. These activation asymmetries of motor areas ipsilateral to the moving hand could not be explained by asymmetries in skill performance, the degree of handedness, or interhemispheric interactions. The latter was measured by a double-pulse transcranial magnetic stimulation paradigm, whereby a conditioning stimulus was applied over one hemisphere and a test stimulus over the other. We propose that the left premotor areas contain action representations strongly related to movement implementation which are also accessed during movements performed with the left body side.
During the past few years, laparoscopy has become the gold standard for some surgical procedures and its applications continue to expand. Because of multiple factors such as loss of tactile perception, two-dimensional visualization of the three-dimensional surgical field, and demanding bimanual hand-eye coordination, special training is required to achieve proficiency with laparoscopy. In this study, as the first step toward evidence-based development of strategies to improve the quality of laparoscopy training from brain activity and behavior relationships, a laparoscopy training simulator was developed for use in functional MRI. Experiments confirmed the functional MRI compatibility of the device. Representative behavioral and functional MRI results for two subjects showed the feasibility of using this simulator to investigate the brain activation associated with components of laparoscopic task performance. To our knowledge, this is the first study that directly looks at the functional MRI brain activation during complex surgical training tasks.
Functional magnetic resonance imaging (fMRI) was used to investigate the neural processing characteristics associated with word retrieval abilities after a phonologically-based treatment for anomia in two stroke patients with aphasia. Neural activity associated with a phonological and a semantic task was compared before and after treatment with fMRI. In addition to the two patients who received treatment, two patients with aphasia who did not receive treatment and 10 healthy controls were also scanned twice. In the two patients who received treatment, both of whose naming improved after treatment, results showed that activation patterns changed after treatment on the semantic task in areas that would have been expected (e.g., left hemisphere frontal and temporal areas). For one control patient, there were no significant changes in brain activation at the second scan; a second control patient showed changes in brain activation at the second scan, on the semantic task, however, these changes were not accompanied with improved performance in naming. In addition, there appeared to be bilateral, or even more right than left hemisphere brain areas activated in this patient than in the treated patients. The healthy control group showed no changes in activation at the second scan. These findings are discussed with reference to the literature on the neural underpinnings of recovery after treatment for anomia in aphasia.
Bone is one of the most transplanted tissues worldwide. Autograft is the ideal bone graft but is not widely used because of donor site morbidity and restricted availability. Allograft is easily accessible but can transmit infections and elicit an immune response.
T cell receptor (TCR) recognition of peptide-MHC class I (pMHC) complexes is a crucial event in the adaptive immune response to pathogens. Peptide epitopes often display a strong dominance hierarchy, resulting in focusing of the response on a limited number of the most dominant epitopes. Such T cell responses may be additionally restricted by particular MHC alleles in preference to others. We have studied this poorly understood phenomenon using Theileria parva, a protozoan parasite that causes an often fatal lymphoproliferative disease in cattle. Despite its antigenic complexity, CD8+ T cell responses induced by infection with the parasite show profound immunodominance, as exemplified by the Tp1(214-224) epitope presented by the common and functionally important MHC class I allele N*01301. We present a high-resolution crystal structure of this pMHC complex, demonstrating that the peptide is presented in a distinctive raised conformation. Functional studies using CD8+ T cell clones show that this impacts significantly on TCR recognition. The unconventional structure is generated by a hydrophobic ridge within the MHC peptide binding groove, found in a set of cattle MHC alleles. Extremely rare in all other species, this feature is seen in a small group of mouse MHC class I molecules. The data generated in this analysis contribute to our understanding of the structural basis for T cell-dependent immune responses, providing insight into what determines a highly immunogenic p-MHC complex, and hence can be of value in prediction of antigenic epitopes and vaccine design.
A functional magnetic resonance imaging (fMRI)-compatible fiber-optic bend sensor was investigated to assess whether the device could be used effectively to monitor opening and closing of the jaw during an fMRI experiment at 3 T. In contrast to surface electromyography, a bend sensor fixed to the chin of the participant is fast and easy to use and is not affected by strong electromagnetic fields. Bend sensor recordings are characterized by high validity (compared with concurrent video recordings of mouth opening) and high reliability (comparing two independent measurements). The results of this study indicate that a bend sensor is able to record the opening and closing of the jaw associated with different overt speech conditions (producing the utterances /a/, /pa/, /pataka/) and the opening of the mouth without speech production. Data post-processing such as filtering was not necessary. There are several potential applications for bend sensor recordings of speech-related jaw movements. First, bend sensor recordings are a valuable tool to assess behavioral performance, such as response latencies, accuracies, and completion times, which is particularly important in children, seniors, or patients with various neurological or psychiatric conditions. Second, the timing information provided by bend sensor data may improve the predicted hemodynamic response that is used for fMRI analysis based on the general linear model (GLM). Third, bend sensor recordings may be included in GLM analyses not for statistical contrast purposes, but as a covariate of no interest, accounting for part of the data variance to model fMRI artifacts due to motion outside the field of view.
"Real-time" functional magnetic resonance imaging is starting to be used in neurofeedback applications, enabling individuals to regulate their brain activity for therapeutic purposes. These applications use two-dimensional multislice echo planar or spiral readouts to image the entire brain volume, often with a much smaller region of interest within the brain monitored for feedback purposes. Given that such brain activity should be sampled rapidly, it is worthwhile considering alternative functional magnetic resonance imaging pulse sequences that trade spatial resolution for temporal resolution. We developed a prototype sequence localizing a column of magnetization by outer volume saturation, from which densely sampled transverse relaxation time decays are obtained at coarse voxel locations using an asymmetric gradient echo train. For 5×20×20 mm3 voxels, 256 echoes are sampled at ?1 msec and then combined in weighted summation to increase functional magnetic resonance imaging signal contrast. This multiecho coarse voxel pulse sequence is shown experimentally at 1.5 T to provide the same signal contrast to noise ratio as obtained by spiral imaging for a primary motor cortex region of interest, but with potential for enhanced temporal resolution. A neurofeedback experiment also illustrates measurement and calculation of functional magnetic resonance imaging signals within 1 sec, emphasizing the future potential of the approach.
Existing live attenuated classical swine fever virus (CSFV) vaccines provide a rapid onset of complete protection but pose problems in discriminating infected amongst vaccinated animals. With a view to providing additional information on the cellular mechanisms that may contribute to protection, which in turn may aid the development of the next generation of CSFV vaccines, we explored the kinetics of the cytokine responses from peripheral blood cells of pigs vaccinated with an attenuated C-strain vaccine strain and/or infected with a recent CSFV isolate. Peripheral blood cells were isolated over the course of vaccination/infection and stimulated in vitro with C-strain or UK2000/7.1 viruses. Virus-specific responses of peripheral blood cells isolated from C-strain vaccinated pigs were dominated by the production of IFN-gamma. IFN-gamma production in response to the C-strain virus was first detected in vaccinates 9 days post-vaccination and was sustained over the period of observation. In contrast, cells from challenge control animals did not secrete IFN-gamma in response to stimulation with C-strain or UK2000/7.1 viruses. Supernatants from UK2000/7.1 infected animals contained significant levels of pro-inflammatory cytokines from day 8 post-infection and these cytokines were present in both virus and mock stimulated cultures. The results suggest that the C-strain virus is a potent inducer of a type-1 T cell response, which may play a role in the protection afforded by such vaccines, whereas the pro-inflammatory cytokine responses observed in cultures from infected pigs may reflect a pathological pro-inflammatory cascade initiated in vivo following the replication and spread of CSFV.
Platelet-derived growth factor (PDGF) has been shown in vivo to increase bone formation and supplement fracture healing, and may have a role as a therapeutic agent in the treatment of bone loss and fracture healing in humans.
Alterations of existing neural networks during healthy aging, resulting in behavioral deficits and changes in brain activity, have been described for cognitive, motor, and sensory functions. To investigate age-related changes in the neural circuitry underlying overt non-lexical speech production, functional MRI was performed in 14 healthy younger (21-32 years) and 14 healthy older individuals (62-84 years). The experimental task involved the acoustically cued overt production of the vowel /a/ and the polysyllabic utterance /pataka/. In younger and older individuals, overt speech production was associated with the activation of a widespread articulo-phonological network, including the primary motor cortex, the supplementary motor area, the cingulate motor areas, and the posterior superior temporal cortex, similar in the /a/ and /pataka/ condition. An analysis of variance with the factors age and condition revealed a significant main effect of age. Irrespective of the experimental condition, significantly greater activation was found in the bilateral posterior superior temporal cortex, the posterior temporal plane, and the transverse temporal gyri in younger compared to older individuals. Significantly greater activation was found in the bilateral middle temporal gyri, medial frontal gyri, middle frontal gyri, and inferior frontal gyri in older vs. younger individuals. The analysis of variance did not reveal a significant main effect of condition and no significant interaction of age and condition. These results suggest a complex reorganization of neural networks dedicated to the production of speech during healthy aging.
Although immunodominance of CD8(+) T-cell responses is a well-recognised feature of viral infections, its role in responses to more antigenically complex pathogens is less clear. In previous studies we have observed that CD8(+) T-cell responses to Theileria parva exhibit different patterns of parasite strain specificity in cattle of different MHC genotypes. In the current study, we demonstrated that animals homozygous for the A10 and A18 MHC haplotypes have detectable responses to only one of 5 T. parva antigens. Over 60% of the responding T cells from the A18(+) and A10(+) animals recognised defined epitopes in the Tp1 and Tp2 antigens, respectively. Comparison of T-cell receptor beta chain expression profiles of CD8(+) T-cell lines and CD8(+) T cells harvested ex vivo confirmed that the composition of the T-cell lines was representative of the in vivo memory CD8(+) T-cell populations. Analysis of the Tp1 and Tp2 antigens revealed sequence polymorphism, which was reflected by differential recognition by T-cell lines. In conclusion, we have demonstrated a profound immunodominance in the CD8(+) T-cell response to T. parva, which we propose is a major determinant of the parasite strain specificity of the response and hence immune protection.
The cause of Crohns disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of (111)In-labeled neutrophils at these sites and clearance of (32)P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway.
We report an unusual pattern of a peri and intra-articular knee fracture following ACL reconstruction. The pattern of injury was opposite to the graft tunnels which contradicts the well established iatrogenic stress riser theory which has been extensively described in the literature. The fractures were reduced anatomically by open means, the graft was found intact and preserved and the fractures were fixed internally protecting the graft and the tunnels. The patient made an uneventful recovery and the post operative MRI scan 12 months later demonstrated bone healing and an intact ACL. When the ACL graft is found intact in this type of injury, the fracture should be fixed around it taking care not to jeopardize its integrity or the tunnels.
In recent years, computer technology has evolved such that highly realistic virtual environments (VEs) can be used within a lab setting. Such VEs provide controlled ability to examine behavioral performance across different populations. The primary goal of this investigation was to examine the ability of mild cognitive impaired (MCI) participants to navigate effectively through a realistic, fictional virtual city. A total of 26 healthy control participants (age: 69 +/- 7.7 years; Mini-Mental State Examination, MMSE >or= 29) and 8 MCI patients (age: 72 +/- 7 years, MMSE >or= 26) were recruited. Both groups exhibited similar spatial-navigation ability. However, the MCI groups ability to use effective visually guided navigation to traverse the VE was significantly compromised compared to healthy controls; a similar performance reduction was also observed when selecting appropriate paths. Though initially groups appear practically indistinguishable in regard to spatially navigating their way through the VE, these data indicate that careful evaluations of behavior in VEs may provide novel ways to differentiate between populations that have historically displayed relatively subtle differences.
The authors aim to identify any benefits or limitations of psychiatric residents attending a Balint-style case discussion group, to explore those experiences, to study the process of the learning experience, and to identify potential educational implications.
Behaviour and fMRI brain activation patterns were compared during encoding and recognition tasks in mild cognitive impairment (MCI) (n=14) and normal controls (NC) (n=14). Deep (natural vs. man-made) and shallow (color vs. black and white) decisions were made at encoding and pictures from each condition were presented for yes/no recognition 20 min later. MCI showed less inferior frontal activation during deep (left only) and superficial encoding (bilaterally) and in both medial temporal lobes (MTL). When performance was equivalent (recognition of words encoded superficially), MTL activation was similar for the two groups, but during recognition testing of deeply encoded items NC showed more activation in both prefrontal and left MTL region. In a region of interest analysis, the extent of activation during deep encoding in the parahippocampi bilaterally and in left hippocampus correlated with subsequent recognition accuracy for those items in controls but not in MCI, which may reflect the heterogeneity of activation responses in conjunction with different degrees of pathology burden and progression status in the MCI group.
Gardnerella vaginalis is a facultative anaerobic Gram-variable pleomorphic rod that forms part of the normal vaginal flora. It is most commonly associated with infection of the genital tract in women, but recognition of extravaginal G. vaginalis infection is becoming more frequent. We describe an unusual case of G. vaginalis vertebral osteomyelitis and discitis in a 38-year-old woman with no apparent predisposing factors.
Using agonists that selectively stimulate PGE2 receptors, the adverse effects that have limited the clinical utility of PGE2 can be avoided and there may be potential for their use as therapeutic agents in the treatment of bone loss in humans.
This study assessed the convergent validity of a virtual environment (VE) navigation learning task, the Groton Maze Learning Test (GMLT), and selected traditional neuropsychological tests performed in a group of healthy elderly adults (n = 24). The cohort was divided equally between males and females to explore performance variability due to sex differences, which were subsequently characterized and reported as part of the analysis. To facilitate performance comparisons, specific "efficiency" scores were created for both the VE navigation task and the GMLT. Men reached peak performance more rapidly than women during VE navigation and on the GMLT and significantly outperformed women on the first learning trial in the VE. Results suggest reasonable convergent validity across the VE task, GMLT, and selected neuropsychological tests for assessment of spatial memory.
Immersive virtual reality (VR) is an innovative tool that can allow study of human spatial navigation in a realistic but controlled environment. The purpose of this study was to examine age- and Alzheimers disease-related differences in route learning and memory using VR.
Periprosthetic femoral fractures around a total knee arthroplasty present a surgical challenge in octogenarians with advanced osteoporosis. We describe a salvage technique combining retrograde intramedullary nailing augmented with polymethylmethacrylate cement in 5 patients followed up for a median time of 12 months. The nail/cement construct bridges the femoral canal tightly and simulates a stemmed cemented revision component. All patients had an uncomplicated recovery and returned to their preinjury functional status within 4 months. This procedure does not disrupt the soft tissue envelope around the fracture site, is easy to perform and permits immediate full range of movement. When standard retrograde nailing or plating alone is inadequate in maintaining severely osteoporotic fracture reduction, nailed cementoplasty is proposed as a salvage procedure in octogenarians unfit for lengthy interventions.
Immunity to the bovine apicomplexan parasite Theileria parva is associated with MHC-I restricted CD8+ T cell responses directed against the intralymphocytic schizont stage of the parasite. A number of schizont-stage antigens that are targets of CD8+ T cell responses from immune animals have been identified but an effective delivery strategy that consistently induces protective CD8+ T cell responses remains to be developed. This study aimed to determine whether fusing Tat, a cell penetrating peptide (CPP) from HIV-1 TAT, to a CD8+ T cell target antigen from T. parva (Tp2) enhances the cytosolic delivery and subsequent stimulation of bovine CD8+ T cell responses in vitro. Using IFN-gamma ELISpot and cytotoxicity assays, it was demonstrated that recombinant Tat-Tp2 fusion protein possessed a superior ability to access MHC-I processing and presentation pathway and to stimulate CD8+ T cell responses compared to recombinant Tp2 protein. Exposure of APC to Tat-Tp2 protein for only 30 min was sufficient for protein uptake and stimulation of CD8+ T cells. This work describes for the first time the utility of a CPP to enhance MHC-I presentation in a veterinary species and supports the evaluation of CPP fusion proteins in the induction of CD8+ T cell responses in vivo.
This paper provides a theoretical assessment of the safety considerations encountered in the simultaneous use of transcranial magnetic stimulation (TMS) and neurological interventions involving implanted metallic electrodes, such as electrocorticography. Metal implants are subject to magnetic forces due to fast alternating magnetic fields produced by the TMS coil. The question of whether the mechanical movement of the implants leads to irreversible damage of brain tissue is addressed by an electromagnetic simulation which quantifies the magnitude of imposed magnetic forces. The assessment is followed by a careful mechanical analysis determining the maximum tolerable force which does not cause irreversible tissue damage. Results of this investigation provide useful information on the range of TMS stimulator output powers which can be safely used in patients having metallic implants. It is shown that conventional TMS applications can be considered safe when applied on patients with typical electrode implants as the induced stress in the brain tissue remains well below the limit of tissue damage.
Porcine reproductive and respiratory syndrome virus (PRRSV) is difficult to control due to a high mutation rate and the emergence of virulent strains. The objective of this study was to analyze the immunological and pathological responses after infection with the European subtype 3 strain Lena in comparison to subtype 1 strains Belgium A and Lelystad-Ter Huurne (LV). Sixteen pigs were inoculated per strain, and sixteen pigs with PBS. At days 7 and 21 post-inoculation (p.i.), four pigs per group were immunized with an Aujeszky disease vaccine (ADV) to study the immune competence after PRRSV infection. Infection with the Lena strain resulted in fever and clinical signs. This was not observed in the Belgium A or LV-infected pigs. Infection with the Lena strain resulted in high virus titers in serum, low numbers of IFN-? secreting cells, a change in leukocyte populations and a delayed antibody response to immunization with ADV. Levels of IL-1?, IFN-?, IL-10, IL-12, TNF-? and IFN-? mRNA of the Lena-infected pigs were increased during the first week of infection. For pigs infected with the Belgium A or LV strain, the effects of infection on these parameters were less pronounced, although for the Belgium A-infected pigs, the level of the analyzed cytokines, except for TNF-?, and leukocyte populations were comparable to the Lena-infected pigs. These results suggest that while the outcome of infection for the three strains was comparable, with mostly clearance of viremia at day 33 p.i, differences in immune responses were observed, perhaps contributing to their virulence.
Although CD1d and NKT cells have been proposed to have highly conserved functions in mammals, data on functions of CD1d and NKT cells in species other than humans and rodents are lacking. Upon stimulation with the CD1d-presented synthetic antigen ?-galactosylceramide, human and rodent type I invariant NKT cells release large amounts of cytokines. The two bovine CD1D (boCD1D) genes have structural features that suggest that they cannot be translated into functional proteins expressed on the cell surface. Here we provide evidence that despite an intron-exon structure and signal peptide that are different from all other known CD1 genes, boCD1D can be translated into a protein that is expressed on the cell surface. However, in vivo treatment of cattle (Bos taurus) with 0.1, 1, or 10 µg kg?¹ of the most commonly used ?-galactosylceramide, which has a C26 fatty acid, did not lead to an increase in body temperature and serum cytokine levels of the animals. This lack of reactivity is not due to a complete inability of boCD1d to present glycosphingolipids because ?-galactosylceramide variants with shorter fatty acids could be presented by boCD1d to human NKT cells in vitro. This suggests that the natural ligands of boCD1d are smaller lipids.
There is a continuing need to improve understanding of the central nervous system control of learning. Specifically, there is a need to examine the characteristics of cortical and sub-cortical activity linked to the stages of motor learning, including those occurring within a single-session. In this study we sought to design and investigate a visuomotor task to determine its ability to assess the component of motor learning occurring during a single session of fMRI (i.e., the online improvement in motor performance). Fourteen healthy control subjects performed a visuomotor task requiring a combination of bilateral grip force to accurately move a cursor towards a target. We assessed online motor learning by comparing behavioural measures (accuracy and error magnitude) and the extent of spatial activation in specific brain regions of interest (ROIs) using fMRI pre- and post-training. Results showed a training-related improvement in performance based on increased accuracy (p<0.0125) and decreased error magnitude (p<0.0125) from pre- to post-training. Decreases in the extent of spatial activation from pre- to post-training in the majority of ROIs supported a training-related attenuation in brain activity associated with online motor learning. Importantly, decreases in error magnitude across conditions (p<0.05) confirmed that improvements in performance continued over the entire course of the experiment. Establishing this task may permit more extensive study of the neural correlates of single-session, online learning in healthy individuals and those with motor control challenges. Information obtained from such studies may provide an opportunity to improve interventions in neurological rehabilitation.
Head motion artifacts are a major problem in functional MRI that limit its use in neuroscience research and clinical settings. Real-time scan-plane correction by optical tracking has been shown to correct slice misalignment and nonlinear spin-history artifacts; however, residual artifacts due to dynamic magnetic field nonuniformity may remain in the data. A recently developed correction technique, Phase Labeling for Additional Coordinate Encoding, can correct for absolute geometric distortion using only the complex image data from two echo planar images with slightly shifted k-space trajectories. An approach is presented that integrates Phase Labeling for Additional Coordinate Encoding into a real-time scan-plane update system by optical tracking, applied to a tissue-equivalent phantom undergoing complex motion and an functional MRI finger tapping experiment with overt head motion to induce dynamic field nonuniformity. Experiments suggest that such integrated volume-by-volume corrections are very effective at artifact suppression, with potential to expand functional MRI applications.
Blood oxygenation level-dependent (BOLD) signal time courses in functional magnetic resonance imaging are estimated within the framework of general linear modeling by convolving an input function, that represents neural activity, with a canonical hemodynamic response function (HRF). Here we investigate the performance of different neural input functions and latency-optimized HRFs for modeling BOLD signals in response to vibrotactile somatosensory stimuli of variable durations (0.5, 1, 4, 7 s) in 14 young, healthy adults who were required to make button press responses at each stimulus cessation. Informed by electrophysiology and the behavioral task, three nested models with an increasing number of parameters were considered: a boxcar; boxcar and offset transient; and onset transient, boxcar and offset transient (TBT). The TBT model provided the best fit of the group-averaged BOLD time courses based on ?(2) and F statistics. Only the TBT model was capable of fitting the bimodal shape of the BOLD response to the 7-s stimulus and the relative peak amplitudes for all stimulus lengths in key somatosensory and motor areas. This suggests that the TBT model provides a more comprehensive description of brain sensorimotor responses in this experiment than provided by the simple boxcar model. Work comparing the activation maps obtained with the TBT model with magnetoencephalography data is under way.
Functional MRI neurofeedback (fMRI NF) is an emerging technique that trains subjects to regulate their brain activity while they manipulate sensory stimulus representations of fMRI signals in "real-time". Here we report an fMRI NF study of brain activity associated with kinesthetic motor imagery (kMI), analyzed using partial least squares (PLS), a multivariate analysis technique. Thirteen healthy young adult subjects performed kMI involving each hand separately, with NF training targeting regions of interest (ROIs) in the left and right primary motor cortex (M1). Throughout, subjects attempted to maximize a laterality index (LI) of brain activity-the difference in activity between the contralateral ROI (relative to the hand involved in kMI) and the ipsilateral M1 ROI-while receiving real-time updates on a visual display. Six of 13 subjects were successful in increasing the LI value, whereas the other 7 were not successful and performed similarly to 5 control subjects who received sham NF training. Ability to suppress activity in the ipsilateral M1 ROI was the primary driver of successful NF performance. Multiple PLS analyses depicted activated networks of brain regions involved with imagery, self-awareness, and feedback processing, and additionally showed that activation of the task positive network was correlated with task performance. These results indicate that fMRI NF of kMI is capable of modulating brain activity in primary motor regions in a subset of the population. In the future, such methods may be useful in the development of NF training methods for enhancing motor rehabilitation following stroke.
A variety of preprocessing techniques are available to correct subject-dependant artifacts in fMRI, caused by head motion and physiological noise. Although it has been established that the chosen preprocessing steps (or "pipeline") may significantly affect fMRI results, it is not well understood how preprocessing choices interact with other parts of the fMRI experimental design. In this study, we examine how two experimental factors interact with preprocessing: between-subject heterogeneity, and strength of task contrast. Two levels of cognitive contrast were examined in an fMRI adaptation of the Trail-Making Test, with data from young, healthy adults. The importance of standard preprocessing with motion correction, physiological noise correction, motion parameter regression and temporal detrending were examined for the two task contrasts. We also tested subspace estimation using Principal Component Analysis (PCA), and Independent Component Analysis (ICA). Results were obtained for Penalized Discriminant Analysis, and model performance quantified with reproducibility (R) and prediction metrics (P). Simulation methods were also used to test for potential biases from individual-subject optimization. Our results demonstrate that (1) individual pipeline optimization is not significantly more biased than fixed preprocessing. In addition, (2) when applying a fixed pipeline across all subjects, the task contrast significantly affects pipeline performance; in particular, the effects of PCA and ICA models vary with contrast, and are not by themselves optimal preprocessing steps. Also, (3) selecting the optimal pipeline for each subject improves within-subject (P,R) and between-subject overlap, with the weaker cognitive contrast being more sensitive to pipeline optimization. These results demonstrate that sensitivity of fMRI results is influenced not only by preprocessing choices, but also by interactions with other experimental design factors. This paper outlines a quantitative procedure to denoise data that would otherwise be discarded due to artifact; this is particularly relevant for weak signal contrasts in single-subject, small-sample and clinical datasets.
Live attenuated C-strain classical swine fever viruses (CSFV) provide a rapid onset of protection, but the lack of a serological test that can differentiate vaccinated from infected animals limits their application in CSF outbreaks. Since immunity may precede antibody responses, we examined the kinetics and specificity of peripheral blood T cell responses from pigs vaccinated with a C-strain vaccine and challenged after five days with a genotypically divergent CSFV isolate. Vaccinated animals displayed virus-specific IFN-? responses from day 3 post-challenge, whereas, unvaccinated challenge control animals failed to mount a detectable response. Both CD4(+) and cytotoxic CD8(+) T cells were identified as the cellular source of IFN-?. IFN-? responses showed extensive cross-reactivity when T cells were stimulated with CSFV isolates spanning the major genotypes. To determine the specificity of these responses, T cells were stimulated with recombinant CSFV proteins and a proteome-wide peptide library from a related virus, BVDV. Major cross-reactive peptides were mapped on the E2 and NS3 proteins. Finally, IFN-? was shown to exert potent antiviral effects on CSFV in vitro. These data support the involvement of broadly cross-reactive T cell IFN-? responses in the rapid protection conferred by the C-strain vaccine and this information should aid the development of the next generation of CSFV vaccines.
Pre-emptive culling is becoming increasingly questioned as a means of controlling animal diseases, including classical swine fever (CSF). This has prompted discussions on the use of emergency vaccination to control future CSF outbreaks in domestic pigs. Despite a long history of safe use in endemic areas, there is a paucity of data on aspects important to emergency strategies, such as how rapidly CSFV vaccines would protect against transmission, and if this protection is equivalent for all viral genotypes, including highly divergent genotype 3 strains. To evaluate these questions, pigs were vaccinated with the Riemser® C-strain vaccine at 1, 3 and 5 days prior to challenge with genotype 2.1 and 3.3 challenge strains. The vaccine provided equivalent protection against clinical disease caused by for the two challenge strains and, as expected, protection was complete at 5 days post-vaccination. Substantial protection was achieved after 3 days, which was sufficient to prevent transmission of the 3.3 strain to animals in direct contact. Even by one day post-vaccination approximately half the animals were partially protected, and were able to control the infection, indicating that a reduction of the infectious potential is achieved very rapidly after vaccination. There was a close temporal correlation between T cell IFN-? responses and protection. Interestingly, compared to responses of animals challenged 5 days after vaccination, challenge of animals 3 or 1 days post-vaccination resulted in impaired vaccine-induced T cell responses. This, together with the failure to detect a T cell IFN-? response in unprotected and unvaccinated animals, indicates that virulent CSFV can inhibit the potent antiviral host defences primed by C-strain in the early period post vaccination.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.